Recombinant antibody fragments as autoantibody antagonists

Abstract

The invention provides methods and compositions for inhibiting autoantibody binding in demyelinating disease such as multiple sclerosis. The compositions comprise immunoglobulin CDR3 sequences derived from combinatorial phage display libraries selected for high-affinity binding to myelin oligodendrocyte glycoprotein.

What is claimed is:  
     
       1. An isolated polypeptide which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair selected from the group consisting of SEQ ID NOS:1 and 2, SEQ ID NOS:3 and 4, SEQ ID NOS:5 and 6, SEQ ID NOS:7 and 8, SEQ ID NOS:9 and 10, and SEQ ID NOS:11 and 12. 
     
     
       2. An isolated polypeptide according to  claim 1 , wherein the polypeptide is an F(ab). 
     
     
       3. A pharmaceutical composition comprising a polypeptide according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       4. A method of inhibiting MOG-antibody binding comprising the step of contacting a mixture of a MOG and an antibody with a polypeptide according to  claim 1 , whereby the MOG-antibody binding is inhibited. 
     
     
       5. A method of inhibiting MOG-antibody binding comprising the step of contacting a mixture of a MOG and an antibody with a polypeptide according to  claim 2 , whereby the MOG-antibody binding is inhibited. 
     
     
       6. A method of inhibiting demyelination associated with the binding of an autoantibody to a MOG polypeptide, comprising the step of administering to a marmoset or human host, subject to a pathogenic MOG polypeptide-polyclonal autoantibody binding, an effective amount of a composition comprising a polypeptide according to  claim 1  not having a functional Fc portion and sufficient to specifically bind the MOG polypeptide and competitively inhibit the binding of the autoantibody to the MOG polypeptide, whereby the demyelination is inhibited. 
     
     
       7. A method of inhibiting demyelination associated with the binding of an autoantibody to a MOG polypeptide, comprising the step of administering to a marmoset or human host, subject to a pathogenic MOG polypeptide-polyclonal autoantibody binding, an effective amount of a composition comprising a polypeptide according to  claim 2  not having a functional Fc portion and sufficient to specifically bind the MOG polypeptide and competitively inhibit the binding of the auto antibody to the MOG polypeptide, whereby the demyelination is inhibited. 
     
     
       8. A method of inhibiting demyelination associated withy the binding of an autoantibody to a MOG polypeptide, comprising the step of administering to a marmoset or human host, subject to a pathogenic MOG polypeptide-polyclonal autoantibody binding, an effective amount of a composition comprising a plurality of polypeptides according to  claim 1  not having a functional Fc portion and sufficient to specifically bind the MOG polypeptide and competitively inhibit the binding of the autoantibody to the MOG polypeptide, whereby the demyelination is inhibited, wherein each of the plurality of polypeptides specifically binds a different MOG eptiope. 
     
     
       9. A method of inhibiting demyelination associated with the binding of an autoantibody to a MOG polypeptide, comprising the step of administering to a marmoset or human host, subject to a pathogenic MOG polypeptide-polyclonal autoantibody binding, an effective amount of a composition comprising a plurality of polypeptides according to  claim 2  not having a functional Fc portion and sufficient to specifically bind the MOG polypeptide and competitively inhibit the binding of the autoantibody to the MOG polypeptide, whereby the demyelination is inhibited, wherein each of the plurality of polypeptides specifically binds a different MOG eptiope. 
     
     
       10. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:1 and 2. 
     
     
       11. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:3 and 4. 
     
     
       12. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:5 and 6. 
     
     
       13. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:7 and 8. 
     
     
       14. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:9 and 10. 
     
     
       15. An isolated polypeptide according to  claim 1 , which specifically binds human myelin oligodendrocyte glycoprotein (MOG), said polypeptide comprising a pair of first and second antigen binding domain sequences, said pair being SEQ ID NOS:11 and 12.